FIELD: pharmaceutical industry.
SUBSTANCE: compound represented by formula (I) or a tautomer or pharmaceutically acceptable salt thereof, wherein Het is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl or their N-oxide; R1 is attached to a carbon atom and is independently selected from hydroxy, halogen, nitrile, C1-4alkyl, C1-4alkoxy, C2-4alkynyl, -O0.1-(CRxRy)v-CO2H and -SO2-CH3; R2 is selected from hydrogen, C1-4alkyl, C2-6alkenyl and hydroxyC1-4alkyl; s is selected from 0 and 1; R3 is a hydrogen or -(A)t-(CRxRy)q-X; t is selected from 0 and 1; q is selected from 0, 1 and 2; wherein if R3 is -(A)t-(CRxRy)q-X then (i) at least one of s, t and q is not 0 and (ii) when t is 0 then s is equal to 1 and q is not equal to 0; A is a C3-6cycloalkylene group or a heterocyclic group containing 3-6 ring members, wherein this heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O, S and their oxidized forms; X is selected from hydrogen, halogen, -CN, -OR9, -S(O)d-Rx, -C(=O)-C1-4alkyl, -NRxRy, -NRxCORy and -C(=O)NRxRy; R4 is selected from halogen; R5 is independently selected from halogen, C1-4alkyl, nitrile, halogenC1-4alkyl, and halogenC1-4alkoxy; R6 and R7 are independently selected from hydrogen, C1-6alkyl, halogenC1-6alkyl, C2-6alkenyl, hydroxyC1-6alkyl, -(CH2)j-O-C1-6alkyl, -(CH2)j-O-(hydroxyC1-6alkyl), -C1-6alkyl-NRxRy, -(CRxRy)p-CONRxRy, -(CRxRy)p-NRxCORy, -(CRxRy)p-O-CH2-CONRxRy, a heterocyclic group containing 3-6 ring members, -CH2-heterocyclic group containing 3-7 ring members, -CH2-O-heterocyclic group containing 3-6 ring members, -CH2-NH-heterocyclic group containing 3-6 ring members, -CH2-N(C1-6alkyl)-heterocyclic group containing 3- 6 ring members, -C(=O)NH-heterocyclic group containing 3-6 ring members, and C3-8cycloalkyl, where these cycloalkyl or heterocyclic groups may be optionally substituted with one or more Rz groups and where in each case the heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O, S and their oxidized forms; R9 is selected from hydrogen, C1-6alkyl, hydroxyC1-6alkyl and -(CH2)k-CO2H; a, j, d, e, n, r and p are independently selected from 0, 1 and 2; k and m are independently selected from 1 and 2; and v is independently selected from 0 and 1. Compounds are prepared by reacting a compound represented by formula (XXXIII) with an organometallic reagent of formula R7M, where Het, R1, R2, R3, R4, R5, R6, R7, a, s, m and n are as defined above and where M is a metal. The invention also relates to a combination and pharmaceutical composition inhibiting the interaction of MDM2-p53, containing an effective amount of a compound represented by formula (I).
EFFECT: isoindolin-1-one derivatives inhibiting MDM2-p53 interaction.
47 cl, 1 tbl, 580 ex
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